EPLERENONE
Clinical safety rating: caution
Animal studies have proved adverse effects but may be safe for humans
Selective aldosterone receptor antagonist (mineralocorticoid receptor antagonist). Binds to the mineralocorticoid receptor, blocking the effects of aldosterone, leading to decreased sodium reabsorption and potassium excretion in the kidney.
| Metabolism | Hepatic metabolism primarily via CYP3A4; also minor involvement of CYP2C8. |
| Excretion | Approximately 67% of an oral dose is excreted in urine as metabolites (primarily inactive glucuronide conjugates) and approximately 32% in feces via biliary elimination; less than 5% of the dose is excreted unchanged in urine. |
| Half-life | Terminal elimination half-life is approximately 4 to 6 hours; in patients with heart failure or renal impairment, half-life may be prolonged (up to 8-12 hours). The short half-life supports twice-daily dosing. |
| Protein binding | Approximately 49-50% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Apparent volume of distribution is 0.6 to 0.7 L/kg, suggesting distribution into total body water and some tissue binding. |
| Bioavailability | Oral bioavailability is approximately 69% under fed conditions; food increases absorption (by about 20-30%) compared to fasting, so it should be taken consistently with or without meals. |
| Onset of Action | After oral administration, serum potassium elevation begins within 2 to 4 hours; maximal reduction in blood pressure (antihypertensive effect) may require 2 to 4 weeks of continuous therapy. |
| Duration of Action | The effect on serum potassium persists for about 12 to 24 hours after a single dose; continuous dosing is required to maintain aldosterone blockade. The antihypertensive effect is sustained with regular twice-daily dosing. |
50 mg orally once daily, may increase to 50 mg twice daily after 4 weeks if tolerated; maximum 100 mg daily.
| Dosage form | TABLET |
| Renal impairment | GFR 30-49 mL/min: 25 mg once daily initially, then 25 mg twice daily as tolerated. GFR <30 mL/min: not recommended. |
| Liver impairment | Child-Pugh class A: no adjustment. Child-Pugh class B: safety not established; consider contraindication due to hyperkalemia risk. Child-Pugh class C: contraindicated. |
| Pediatric use | Not FDA approved for pediatric use; safety and efficacy not established. |
| Geriatric use | Start at 25 mg once daily; monitor serum potassium and renal function closely due to age-related decline in GFR. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Strong CYP3A4 inhibitors (eg ketoconazole) are contraindicated Can cause hyperkalemia particularly in patients with renal impairment.
| Breastfeeding | No data are available on the presence of eplerenone in human milk, effects on the breastfed infant, or effects on milk production. The milk-to-plasma ratio is unknown. Eplerenone is highly protein-bound (>90%), which may limit secretion into milk, but due to potential adverse effects (e.g., electrolyte imbalances, hypotension), breastfeeding is not recommended during therapy. |
| Teratogenic Risk | Eplerenone is contraindicated in pregnancy. Animal studies have shown embryotoxicity and fetotoxicity at doses below the human dose. In rats, increased fetal resorptions, reduced fetal weights, and delayed ossification were observed. No adequate human studies exist. Risk cannot be ruled out, but due to the mechanism (aldosterone antagonism) and animal data, potential fetal harm is significant. Avoid use in pregnant women, especially during the first trimester, as it can cause renin-angiotensin system effects impacting fetal renal development and oligohydramnios. |
■ FDA Black Box Warning
None.
| Common Effects | hypertension |
| Serious Effects |
["Serum potassium >5.5 mEq/L at initiation","Type 2 diabetes with microalbuminuria","Severe renal impairment (CrCl <30 mL/min)","Concomitant use with potassium-sparing diuretics or strong CYP3A4 inhibitors"]
| Precautions | ["Hyperkalemia: risk increased in patients with renal impairment, diabetes, or taking other potassium-sparing drugs.","Renal impairment: not recommended if eGFR <30 mL/min/1.73 m².","Hypotension and electrolyte imbalances.","Avoid use with strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir)."] |
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| Fetal Monitoring | If inadvertent exposure occurs during pregnancy, monitor fetal renal function via ultrasound for oligohydramnios, fetal growth, and amniotic fluid index. Monitor maternal blood pressure, serum potassium, and renal function. Newborns exposed in utero should be monitored for hypotension, hyperkalemia, and renal impairment. |
| Fertility Effects | In animal studies, eplerenone had no effects on male or female fertility at doses up to 1000 mg/kg/day. No human studies on fertility are available. However, as an aldosterone antagonist, it may theoretically affect hormonal balance, but no significant impact on human fertility has been reported. |